JP2021181501A - Methods for treating immunodeficiency diseases - Google Patents

Abstract

To provide methods for treating immunodeficiency diseases.SOLUTION: The invention relates to a method for treating a patient with WHIM syndrome or related disorders such as myelokathexis, comprising the administration of X4P-001 to decrease CXCR4 activity. The method demonstrates surprising effectiveness, with comparatively little toxicity. In one embodiment, the X4P-001 or pharmaceutically acceptable salt thereof is administered at a dose of from about 25 mg/day to about 150 mg/day. In another embodiment, the patient exhibits warts. In still another embodiment, cells taken from the patient exhibit expression of a mutant form of CXCR4.SELECTED DRAWING: None

Description

INDUSTRIAL APPLICABILITY The present invention relates to methods for treating immunodeficiency diseases, in particular for treating warts, hypogammaglobulinemia, immunodeficiency, myelokathexis (WHIM) syndrome or "WHIMS". Regarding the method. WHIMS is a disease characterized by neutropenia and lymphopenia resulting in skin and genital warts and recurrent infections.

Cross-reference to related applications This application is a US provisional patent application serial number USSN 62 / 271,087 filed December 22, 2015 and USSN 62 / 428,964 filed December 1, 2016 ( All of these claim the benefit of priority to (incorporated herein by reference).

WHIM syndrome is a rare autosomal dominant immunodeficiency disorder that results in multiple mutations that remove 10-19 amino acids from the carboxy terminus of CXCR4, a chemokine receptor expressed by both hematopoietic and non-hematopoietic cells. [Hernandez 2003]. Mutations in the CXCR4 receptor are known to prevent normal release of mature neutrophils from the bone marrow into the blood [Kawai 2005] and cause neutropenia in patients with WHIM syndrome [Dale 2011]. ]. In addition to neutropenia, WHIM syndrome is characterized by lymphopenia affecting circulating T and B cell levels [Balabanian 2012, Dotta 2011], resulting in low levels of immunoglobulins. The exact mechanism for lymphopenia is unknown, but may be due to disruption of normal lymphocyte transport and retention of lymphocytes in the bone marrow and other lymphoid tissues [Ma 1999].
In general, clinical symptoms first appear in early childhood with recurrent bacterial infections due to low levels of leukocytes and antibodies [NORD 2015]. Common infections include otitis media, cellulitis, impetigo, abscesses, bacterial pneumonia, sinusitis, and periodontitis. Affected individuals are particularly susceptible to human papillomavirus (HPV), which can cause widespread warts affecting the hands, feet, face, and trunk and is often refractory [NORD].
2015]. Mucosal and genital warts may also develop, with an increased risk of progression to cervical cancer [NORD 2015]. Recent treatments include G-CSF and intravenous immunoglobulin, which are non-specific, costly, difficult to administer, and only partially effective [Kawai 2009]. Year].

Hernandez et al., Nature Genetics (2003) 34: 70-74 Kawai et al., Exp Hematol. (2005) 33: 460-468 Kawai et al., Curr Opin Hematol. (2009) 16: 20-26

Current treatments available for patients with WHIM syndrome are inadequate. There is a clear unmet need for agents that improve outcomes in the treatment of such patients.

Effective targeting treatments for WHIM syndrome, such as X4P-001, are needed to manage patients. X4P-001 can be administered orally, which makes it an excellent candidate for the chronic treatment setting required for patients with WHIM syndrome, in addition to being a targeted treatment.
The present invention also provides the following items.
(Item 1)
A method for treating WHIM syndrome in a patient in need of treatment for WHIM syndrome, comprising administering to said patient an effective amount of X4P-001 or a pharmaceutically acceptable salt or composition thereof. Method.
(Item 2)
The method of item 1, wherein the X4P-001 or a pharmaceutically acceptable salt thereof is administered at a dose of about 25 mg / day to about 150 mg / day.
(Item 3)
The method of item 1, wherein the patient indicates a wart.
(Item 4)
The method according to any one of items 1 to 3, wherein the cells collected from the patient show the expression of the mutant form of CXCR4.
(Item 5)
The method according to any one of items 1 to 4, wherein the cells collected from the patient show increased expression of CXCR4.
(Item 6)
The method according to any one of items 1 to 5, further comprising a step of obtaining a biological sample from the patient and a step of measuring the amount of a disease-related biomarker.
(Item 7)
The method according to item 6, wherein the biological sample is a blood sample.
(Item 8)
7. The method of item 7, wherein the disease-related biomarker is circulating CXCR4.
(Item 9)
The method according to any one of items 1 to 8, wherein the X4P-001 or a pharmaceutically acceptable salt or composition thereof is orally administered once a day.
(Item 10)
The method according to any one of items 1 to 8, wherein the X4P-001 or a pharmaceutically acceptable salt or composition thereof is orally administered twice a day.
(Item 11)
(A) X4P-001, or a pharmaceutically acceptable salt thereof-about 10-20% by weight of the composition,
(B) Microcrystalline Cellulose-Approximately 70-85% by weight of the composition,
(D) Sodium croscarmellose-about 5-10% by weight of the composition,
(E) Sodium stearyl fumarate-about 0.5-2% by weight of the composition, and (f) Colloidal silicon dioxide-about 0.1-1.0% by weight of the composition.
A unit dosage form comprising a composition comprising.
(Item 12)
The unit dosage form according to item 11, in the form of a capsule.
(Item 13)
The unit dosage form of item 12, wherein the capsule comprises about 25 mg of X4P-001, or a pharmaceutically acceptable salt thereof.
(Item 14)
A method for treating WHIM syndrome in a patient in need of treatment for WHIM syndrome, comprising the step of administering the unit dosage form of item 11 to said patient.
(Item 15)
A method for treating WHIM syndrome in patients in need of treatment for WHIM syndrome, which increases absolute neutrophil count (ANC) to levels greater than or equal to 600 cells / μL and / or absolute. A step of administering to the patient X4P-001 or a pharmaceutically acceptable salt or composition thereof in an amount effective to increase the number of lymphocytes (ALC) to greater than or equal to 1000 cells / μL. Including methods.
(Item 16)
15. The method of item 15, wherein the patient first showed <600 / μL ANC and / or <1000 / μL ALC prior to treatment with X4P-001.
(Item 17)
15. The method of item 15, wherein the patient first showed less than 400 ANCs / μL and / or less than 650 ALCs / μL prior to treatment with X4P-001.
(Item 18)
The method according to any one of items 1 to 10 or 14 to 17, which results in an increase in ANC levels up to at least about 600 pieces / μL in at least 85% of the evaluation.
(Item 19)
The method according to any one of items 1 to 10 or 14 to 18, which results in an increase in ALC of at least about 1000 pieces / μL in at least 85% of the evaluation.
(Item 20)
The method of any one of items 1-10 or 14-19, which results in improved levels of protective antibody in the patient responding to the vaccine.

FIG. 1 shows inhibition by X4P-001 on the binding of SDF-1α to CXCR4 + CEM-CCRF cells.

FIG. 2 shows the inhibition of Eu-GTP binding stimulated by SDF-1α by X4P-001.

^{FIG. 3 shows the inhibition of [35} S] -GTP-γ-S binding stimulated by SDF-1α by X4P-001.

FIG. 4 shows the inhibition of calcium flux induced by SDF-1α by X4P-001.

FIG. 5 shows the inhibition of chemotaxis of CCRF-CEM stimulated by SDF-1α by X4P-001.

FIG. 6 shows the stimulation of calcium flux with SDF-1α in wild-type and CXCR4 variants.

FIG. 7 shows the inhibition of SDF-1α stimulation by X4P-001 in wild-type and CXCR4 variants.

FIG. 8 shows the white blood cell count (A), neutrophil count (B) and lymphocyte count (C) after oral administration of X4P-001 to a male Beagle dog.

FIG. 9 shows a dose-dependent increase in WBC number (2-3 ×) in human subjects receiving X4P-001.

The ligand for the CXCR4 receptor is SDF-1α, which is involved in a number of physiological processes, homing to the bone marrow and playing a central role in hematopoietic cells released from the bone marrow [Lapidot 2002]. Mutations in CXCR4 prevent the normal release of mature neutrophils from the bone marrow into the blood [Kawai 2005]. Bone marrow examination of patients with WHIM syndrome shows abundance of neutrophil remnants in neutrophils with hyperfractionated nuclei and bone marrow macrophages [Bohinjec 1981].

^{Patients with WHIM syndrome who usually have a low white blood cell count of <1.0 × 10 9} / L as a result of disruption of the CXCR4 / SDF-1α axis and with the presence of severe neutropenia and lymphopenia. Occurs [Dale 2011]. The mechanism of CXCR4 / SDF-1α axis failure is described in the following paragraph.

CXCR4 is a G protein-coupled receptor, and association with SDF-1α induces typical activation of the G protein-dependent pathway of chemokine receptors [Baggiolini 1998, Zlotnik 2000]. These processes are regulated in a timely manner by eliminating further activation of G proteins (ie, desensitization) and mobilizing β-arrestin to the receptor, which leads to intracellular translocation of the receptor. Mutants of CXCR4 with WHIM syndrome impair receptor desensitization and intracellular translocation when exposed to SDF-1α, enhancing and prolonging receptor activation [Hernandez].
2003, Balabanian 2005, Gulino 2004, Kawai 2005, Lagane 2008, McCormick 2009]. Prolonging the activity of SDF-1α-dependent signaling is myelogenous seen in WHIM syndrome, as CXCR4 normally regulates leukocyte cell transport and is particularly important for neutrophil adhesion in the bone marrow. Probably a cause for cell retention (MKX) and neutropenia [McDermott 2011-a].

X4P-001 enhances the CXCR4 variant, resulting in an increase in circulating leukocyte count by overcoming the downregulation deficiency (intracellular transfer of the receptor) and receptor dysfunction caused by the CXCR4 variant. It is a small molecule antagonist of CXCR4 that has the potential to block the signal transduction activity (McDermott 2011-b). It was also demonstrated that X4P-001 inhibits the most common genotype morphology of CXCR4 due to WHIM syndrome (R334X and E343X) to the same extent as wild-type CXCR4 [Moshi 2012].

Based on these studies, oral administration of up to 400 mg with BID for 3.5 days (healthy volunteers) and 200 mg with BID for 8-10 days (healthy volunteers and HIV patients) is well tolerated and in any pattern. It was demonstrated that there were no adverse events or clinically significant laboratory changes. These studies also demonstrated pharmacodynamic activity due to dose and concentration-related changes in circulating leukocytes (WBC), as well as high volume distribution (VL) suggesting high tissue penetration.

We have CXCR4 antagonism by X4P-001 to cause irritation, hypogammaglobulinemia (low levels of immunoglobulin), immunodeficiency (susceptibility to infection) and myeloid cell retention (trapping of leukocytes in the bone marrow). It was considered that significant treatment benefits could be obtained in patients with WHIMS, which is an acronym for, as well as individual aspects of WHIMS. Administration of X4P-001 inhibits the binding of SDF-1α to CXCR4 and CXCR4 + CEM-CCRF cells. [See FIG. 1]. Administration of X4P-001 also inhibits CXCR4 cell signaling and SDF-1α-induced calcium flux. [See Figures 2-4]. Thus, X4P-001 inhibits SDF-1α-stimulated CCRF-CEM chemotaxis. [See FIG. 5].

Furthermore, we believe that relatively low toxicity such results can be achieved because the CXCR4 targeting drug is specifically targeted in the normal proliferative cell population and does not induce cell cycle arrest. .. Accordingly, the present invention provides significant advantages in treatment outcomes that take advantage of the low toxicity and action of the CXCR4 inhibitor AMD11070 (X4P-001).

In the present invention, patients with WHIMS, or related syndromes, can be used as a single agent (single agent therapy) or as granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF) or Treated with X4P-001, or a pharmaceutically acceptable salt or composition thereof, in combination with another agent such as intravenous immunoglobulin (IVIG).

In some embodiments, the invention is a method for treating WHIMS in a patient in need thereof, in combination with G-CSF, GM-CSF and / or IVIG, X4P-001 or a pharmacy thereof. Provided are methods comprising the step of administering to said patient a generally acceptable salt or composition. Other treatments that may be utilized in the treatment of WHIMS include bone marrow transplantation and treatment with cord blood stem cells.

In some embodiments, the provided method comprises administering X4P-001, or a pharmaceutically acceptable salt or composition thereof, to a fasting patient.

In certain embodiments, the present invention is a method for treating a patient's WHIMS in need thereof, wherein X4P-001, or a pharmaceutically acceptable salt or composition thereof, is administered to the patient. Provided is a method including a step of obtaining a biological sample from a patient and a step of measuring the amount of a disease-related biomarker. In some embodiments, the biological sample is a blood sample. In certain embodiments, the disease-related biomarker is selected from the group consisting of CXCR4, SDF-1α / CXCL12, and GRK3 (G protein-coupled receptor kinase 3).

In certain embodiments, the present invention is a method for treating a patient's WHIMS in need thereof, wherein X4P-001, or a pharmaceutically acceptable salt or composition thereof, is administered to the patient. Provides a method that includes steps to do.

In some embodiments, X4P-001 or a pharmaceutically acceptable salt thereof is administered at a dose of about 25 mg / day to about 150 mg / day.

In some embodiments, the patient exhibits warts.

In some embodiments, cells harvested from a patient exhibit expression of a mutant form of CXCR4.

In some embodiments, cells harvested from the patient show increased expression of CXCR4.

In some embodiments, the method further comprises obtaining a biological sample from the patient and measuring the amount of disease-related biomarker.

In some embodiments, the biological sample is a blood sample.

In some embodiments, the disease-related biomarker is circulating CXCR4.

In some embodiments, X4P-001 or a pharmaceutically acceptable salt or composition thereof is orally administered once daily.

In some embodiments, X4P-001 or a pharmaceutically acceptable salt or composition thereof is orally administered twice daily.

In some embodiments, the invention is
(A) X4P-001, or a pharmaceutically acceptable salt thereof-about 10-20% by weight of the composition,
(B) Microcrystalline Cellulose-Approximately 70-85% by weight of the composition,
(D) Sodium croscarmellose-about 5-10% by weight of the composition,
(E) Sodium stearyl fumarate-about 0.5-2% by weight of the composition, and (f) Colloidal silicon dioxide-about 0.1-1.0% by weight of the composition.
Provided is a unit dosage form comprising a composition comprising.

In some embodiments, the unit dosage form is in the form of a capsule.

In some embodiments, the capsule comprises about 25 mg of X4P-001, or a pharmaceutically acceptable salt thereof.

In some embodiments, the invention provides a method for treating WHIM syndrome in a patient in need thereof, comprising the step of administering the disclosed unit dosage form to a patient.

In some embodiments, the invention is a method for treating WHIM syndrome in a patient in need thereof, increasing the absolute neutrophil count (ANC) in the patient's, eg, patient's blood. And / or a method comprising the step of administering to said patient X4P-001 or a pharmaceutically acceptable salt or composition thereof in an amount effective to increase absolute lymphocyte count (ALC). In some embodiments, ANC and / or ALC is about 60%, 70%, 80%, 90%, 95 of that of the average healthy human without WHIM syndrome or another immunodeficiency in the patient. %, Or increase to 100%. In some embodiments, ANC and / or ALC is about 60%, 70%, 80%, 90% of the average healthy human being of the same age, weight, and gender as the patient's. , 95%, or up to 100%.

In some embodiments, the invention is a method for treating WHIM syndrome in a patient in need thereof, with an absolute neutrophil count (ANC) greater than or equal to 600 cells / μL. X4P-001 or a pharmaceutically acceptable salt or composition thereof in an amount effective to increase and / or increase the absolute lymphocyte count (ALC) to a level greater than or equal to 1000 cells / μL. Provided is a method comprising the step of administering the substance to the patient.

In some embodiments, the patient initially showed <600 / μL ANC and / or <1000 / μL ALC prior to treatment with X4P-001.

In some embodiments, the patient initially showed less than 400 ANCs / μL and / or less than 650 ALCs / μL prior to treatment with X4P-001.

In some embodiments, the disclosed method is at least about 600 / μL, about 800 / μL, about 1000 / μL, about 1,200 / μL, or successfully, at least 85% of the evaluation. It results in an increase in ANC levels up to the value of humans with a functioning immune system.

In some embodiments, the disclosed method is at least about 1000 / μL, about 1,200 / μL, or about 1,500 / μL, or normally functioning immunity in at least 85% of the evaluation. It results in an increase in ALC up to the value of humans with the system.

In some embodiments, the disclosed method results in improved levels of protective antibody in the patient responding to the vaccine.

In some embodiments, the disclosed method results in a reduced frequency of infection in the patient, such as at least 50% less infection, eg, respiratory tract infection.

In some embodiments, the disclosed method results in increased levels of total circulating WBC, neutrophils, and / or lymphocytes. In some embodiments, the cell number of WBCs, neutrophils, and / or lymphocytes increases to at least 1.4 × baseline. In some embodiments, the cell number of WBCs, neutrophils, and / or lymphocytes increases to at least 1.8 × baseline. In some embodiments, the cell number of WBCs, neutrophils, and / or lymphocytes increases to at least 2.9 × baseline. In some embodiments, the number of lymphocyte cells increases to at least 2.9 x baseline. In some embodiments, the number of neutrophil cells increases to at least 2.7 x baseline and the number of lymphocyte cells increases to 1.9 x baseline.

In some embodiments, the invention is a method of treating WHIMS in a patient in need thereof, in which an effective amount of X4P-001 or a pharmaceutically acceptable salt or composition thereof, warts, HPV. Provided are methods comprising the step of administering to said patient, in conjunction with another treatment for infection or neutropenia.

Dosing and Formulation X4P-001 is a CXCR4 antagonist with molecular formula C21H27N5; molecular weight 349.48amu; appearance white to pale yellow solid; solubility: X4P-001 in the pH range 3.0 to 8.0. It is easily soluble in (> 100 mg / mL), slightly insoluble at pH 9.0 (10.7 mg / mL), and sparingly soluble at pH 10.0 (2.0 mg / mL). X4P-001 is sparingly soluble in water and has a melting point of 108.9 ° C.

The chemical structure of X4P-001 is described below.

In certain embodiments, the composition containing X4P-001 is orally administered in an amount of about 10 mg to about 600 mg daily. In certain embodiments, the dosage composition may be provided twice daily in divided dosages at approximately 12 hour intervals. In other embodiments, the dosage composition may be provided once daily. The terminal phase half-life of X4P-001 has generally been determined to be between about 12 and about 24 hours, or about 14.5 hours. The dosage for oral administration may be from about 10 mg to about 300 mg once or twice daily. In certain embodiments, the dosage of X4P-0001 useful in the present invention is from about 20 mg to about 600 mg daily. In another embodiment, the dosage of X4P-001 useful in the present invention is from about 25 mg to about 200 mg daily, from about 25 mg to about 150 mg daily, from about 25 mg to about 100 mg daily, and about 100 mg daily. It may range from 25 mg to about 50 mg, from about 50 mg to about 150 mg daily, or from about 50 mg to about 100 mg daily.

In some embodiments, the provided method comprises administering to the patient a pharmaceutically acceptable composition comprising X4P-001, the composition being formulated for oral administration. In certain embodiments, the composition is formulated for oral administration in the form of tablets or capsules. In some embodiments, the composition comprising X4P-001 is formulated for oral administration in the form of capsules.

In certain embodiments, the provided method provides a patient with one or more capsules comprising 10 mg to 1200 mg of the X4P-001 active ingredient and one or more pharmaceutically acceptable excipients. Includes the step of administration. In certain embodiments, the capsule is composed of hard gelatin.

In certain embodiments, the present invention relates to X4P-001, or a pharmaceutically acceptable salt thereof, one or more diluents, disintegrants, lubricants, flow aids, and wetting. A composition comprising an agent is provided. In some embodiments, the invention is 10 mg to 1200 mg of X4P-001, or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, calcium hydrogen phosphate dihydrate, sodium croscarmellose, stearyl fumarate. A composition comprising sodium, colloidal silicon dioxide, and sodium lauryl sulfate is provided. In some embodiments, the invention presents 10-200 mg of X4P-001, or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, calcium hydrogen phosphate dihydrate, sodium croscarmellose, stearyl fumarate. Provided are unit dosage forms comprising a composition comprising sodium, colloidal silicon dioxide, and sodium lauryl sulfate. In certain embodiments, the present invention relates to about 10 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, Units comprising a composition comprising X4P-001, or a pharmaceutically acceptable salt thereof, present in an amount of about 600 mg, about 700 mg, about 750 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, or about 1200 mg. Provide shape. In some embodiments, the provided composition (or unit dosage form) is administered to the patient once daily, twice daily, three times daily, or four times daily. In some embodiments, the provided composition (or unit dosage form) is administered to the patient once or twice daily.

In some embodiments, the invention is
(A) X4P-001, or a pharmaceutically acceptable salt thereof-about 10-30% by weight of the composition,
(B) Microcrystalline Cellulose-Approximately 60-80% by weight of the composition,
(C) Sodium croscarmellose-about 5-10% by weight of the composition,
(D) sodium stearyl fumarate-about 0.5-2% by weight of the composition, and (e) colloidal silicon dioxide-about 0.1-1.0% by weight of the composition.
Provided is a unit dosage form comprising a composition comprising.

In some embodiments, the invention is
(A) X4P-001, or a pharmaceutically acceptable salt thereof-about 14.7% by weight of the composition,
(B) Microcrystalline Cellulose-Approximately 78.1% by weight of the composition,
(C) Sodium croscarmellose-about 6.0% by weight of the composition,
(D) Sodium stearyl fumarate-about 1.0% by weight of the composition, and (e) colloidal silicon dioxide-about 0.2% by weight of the composition.
Provided is a unit dosage form comprising a composition comprising.

In some embodiments, the invention is
(A) X4P-001, or a pharmaceutically acceptable salt thereof-about 10-20% by weight of the composition,
(B) Microcrystalline Cellulose-Approximately 25-40% by weight of the composition,
(C) Calcium Hydrogen Phosphate Dihydrate-Approximately 35-55% by weight of the composition,
(D) Sodium croscarmellose-about 4-15% by weight of the composition,
(E) Sodium stearyl fumarate-about 0.3-2% by weight of the composition,
(F) Colloidal Silicon Dioxide-Approximately 0.1-1.5% by Weight of Composition, and (g) Sodium Lauryl Sulfate-Approximately 0.1-1.5% by Weight of Composition
Provided is a unit dosage form comprising a composition comprising.

In some embodiments, the invention is
(A) X4P-001, or a pharmaceutically acceptable salt thereof-about 12.85% by weight of the composition,
(B) Microcrystalline Cellulose-Approximately 31.92% by weight of the composition,
(C) Calcium Hydrogen Phosphate Dihydrate-Approximately 44.4% by weight of the composition,
(D) Sodium croscarmellose-about 8.33% by weight of the composition,
(E) Stearyl fumarate-about 1.38% by weight of the composition,
(F) Colloidal Silicon Dioxide-Approximately 0.42% by Weight of Composition, and (g) Sodium Lauryl Sulfate-Approximately 0.7% by Weight of Composition
Provided is a unit dosage form comprising a composition comprising.

For example, it may be desirable to administer a combination of active compounds for the purpose of treating a particular disease or condition, so that at least one of them is a pharmaceutical composition containing two or more compounds according to the invention. Can be conveniently combined in the form of a kit suitable for co-administration of the composition within the scope of the present invention. Accordingly, the kit of the present invention comprises two or more separate pharmaceutical compositions in which at least one of them contains the compound of the present invention and a means for separately holding the composition, for example, a container. Includes a divided bottle, or a divided foil packet. An example of such a kit is the well-known blister pack used for packaging tablets, capsules and the like.

The kits of the present invention are particularly used to administer different dosage forms (eg, oral and parenteral), administer different compositions at different dosing intervals, or dose different compositions to each other. Are suitable. To promote compliance, the kit typically includes instructions for administration and may be provided with storage aid.

The following examples describe the invention in more detail. The following preparations and examples are provided to allow one of ordinary skill in the art to have a clearer understanding of the invention and practice the invention. However, the invention is not limited in scope by embodiments exemplified solely for the purpose of exemplifying a single aspect of the invention, and methods that are functionally equivalent are within the scope of the invention. Indeed, various modifications of the invention will be apparent to those skilled in the art from the aforementioned description and accompanying drawings in addition to those described herein. Such amendments are intended to be within the scope of the appended claims.

The contents of each document cited herein are incorporated herein by reference in their entirety.

(Example 1: Non-clinical evaluation of the effect of X4P-001 on CXCR4)
In vitro Pharmacology Extensive research on in vitro pharmacology of X4P-001 (formally referred to as AMD11070) and reports of the results [Moshi 2012]. Presented below is relevant information from the Mosi 2012 bibliographic publication. The SDF-1α isoform was used in the experiments described below.

Inhibition of SDF-1α binding to CXCR4 by X4P-001 In a heterologous competitive binding assay, X4P-001 was ^{a CCRF-CEM cell of [125} I] -SDF-1α (a T lymphoblastic cell that naturally expresses CXCR4). It has been shown to inhibit binding to the strain [Crump 1997]). The results of this assay are shown in Figure 2 below. The data were fitted into a single site binding model to give an _{IC 50 of 12.5 ± 1.3 nM.}

Inhibition of CXCR4 Cell Signaling by X4P-001 CXCR4 is a G protein-coupled receptor [Baggiolini 1998, Zlotnik 2000]. Thus, non-hydrolyzable analogs of GTP, such as fluorescently labeled Europium-GTP (Eu-GTP) or radiolabeled [ ³⁵ S] -GTPγS, can be used to measure receptor activation. .. The results shown in FIGS. 3 and 4 show that X4P-001 inhibits CXCR4 activation and is 39.8 ± 2.5 nM and 19.0 ± ^{in the Eu-GTP binding and [35 S] -GTPγS assays, respectively.} showed that having an _{IC 50} value of 4.1 nM.

Upon activation of G protein-coupled receptors, intracellular signaling pathways are induced, resulting in the release of calcium from intracellular storage. This calcium flux can be assayed using Fluo-4, a calcium chelate molecule that fluoresces when bound to calcium. X4P-001 was able to inhibit calcium flux mediated 9.0 SDF-l [alpha] of CCRF-CEM cells with _{an IC 50} of ± 2.0 nM (2.5 nM for SDF-1α). The results are shown in FIG.

An important property of all chemokines is that they induce a chemotactic response to the chemokine concentration gradient. X4P-001, as shown in FIG. 6, with _{an IC 50} of 19.0 ± 4.0 nM, were able to inhibit the chemotaxis mediated SDF-l [alpha] of CCRF-CEM cells.

A summary of the above in vitro results is presented in Table 1 below:

Selectivity of X4P-001 for CXCR4 To demonstrate the specificity of X4P-001 for CXCR4, a calcium signaling assay for a panel of chemokine receptors, and for BLT ₁ , a receptor for leukotriene B4 (LTB ₄ ), and CXCR7. Tested in a ligand binding assay. LTD ₄ is a potent chemical attractant and its receptor is a G protein-coupled receptor. The results in Table 2, CCR1, CCR2b, CCR4, CCR5 , CCR7, CXCR3, and _{IC 50} of X4P-001 for LTB ₄ are in all cases, indicating that was> 50 mM. X4P-001 did not inhibit the binding of SDF-1α to CXCR7 at a concentration of 10 mM, the maximum concentration tested in this assay. Together, these data indicate that X4P-001 is a selective inhibitor of CXCR4.

To demonstrate the specificity of X4P-001 for CXCR4, it was tested in a calcium signaling assay for a panel of chemokine receptors, and in a BLT ₁ , a receptor for leukotriene B4 (LTB ₄ ), and a ligand binding assay for CXCR7. LTD ₄ is a potent chemical attractant and its receptor is a G protein-coupled receptor. The results in Table 2, CCR1, CCR2b, CCR4, CCR5 , CCR7, CXCR3, and _{IC 50} of X4P-001 for LTB ₄ are in all cases, indicating that was> 50 mM. X4P-001 did not inhibit the binding of SDF-1α to CXCR7 at a concentration of 10 mM, the maximum concentration tested in this assay. Together, these data indicate that X4P-001 is a selective inhibitor of CXCR4.

Inhibition of C-Terminal Variant of CXCR4 by X4P-001 From a therapeutic point of view, it is important that the CXCR4 antagonist can act on the CXCR4 variant. Variants in which the carboxy terminus of CXCR4 has been cleaved have been reported in connection with WHIM syndrome, and nonsense mutations result in cleavage of 19 amino acids (R334X) and cleavage of 10 amino acids (E343X), resulting in frameshift mutations. Causes cleavage of 13 amino acids (S339fs342X) [Hernandez 2003, Kawai 2009]. R334X and E343X CXCR4 variants were cloned and transiently expressed in the canine thymocyte cell line Cf2Th. This cell line was selected due to lack of expression of CXCR4 [Wong 2008]. Wild-type CXCR4 was similarly subcloned into this cell line for control studies. Control studies demonstrated that both of these carboxy-terminated variants were able to respond to SDF-1α in a calcium flux assay with similar efficacy to wild-type CXCR4. _{The EC 50} values for SDF-l [alpha] is, CXCR4 wild-type, against the R334X and E343X variants, respectively, were 13.6,11.3 and 15.3 nM (Figure 6). The inhibitory effect of X4P-001 on SDF-1α-mediated calcium flux was evaluated for two CXCR4 variants. Both variants, the wild-type, against the R334X and E343X variants, respectively, was inhibited to a similar extent as the wild-type CXCR4 with _{IC 50} values of 3.1,8.5 and 4.6 nM (Figure 7).

Use the CCRF-CEM cell lines that express the CXCR4 on the consideration and conclusions natural from in vitro studies [Crump 1997 years], X4P-001 is, to CXCR4 at 12.5 ± _{IC 50} of 1.3nM SDF- It has been shown to inhibit 1α ligand binding. X4P-001 also respectively, using any of the fluorescent Eu-GTP or radiolabeled ^[35 S] -GTPyS binding assay with _{IC 50} values of 39.8 ± 2.5 nM and 19.0 ± 4.1 nM two assays, indicated by the inhibition of calcium flux mediated SDF-l [alpha] at _{an IC 50} of inhibition, and 9.0 ± 2.0 nM for G protein activation mediated SDF-l [alpha] of the CXCR4 receptor Thus, it also inhibited the activation and signal transduction of CXCR4. X4P-001 also chemotaxis mediated SDF-l [alpha] with _{an IC 50} of 19.0 ± 4.0 nM, it inhibited the physiological response mediated by CXCR4. In addition, X4P-001 is a calcium flux mediated by either MIP1α, MCP-1, TARC, RANTES, MIP-3β, or IP10, which are ligands for CCR1, CCR2b, CCR4, CCR5, CCR7 and CXCR3, respectively. , Or SDF-1α binding to CXCR7, or LTD4 binding to BLT1, an alternative G protein-coupled receptor that mediates chemotaxis, had little or no inhibitory effect. These data indicate that X4P-001 is a selective inhibitor of CXCR4 against other chemokine receptors being evaluated.

Mutations in CXCR4 that result in cleavage of the intracellular carboxy terminus of the receptor are associated with a rare condition, WHIM syndrome [Hernandez 2003, Kawai 2009]. When two of these CXCR4 variants were evaluated, the results demonstrated that X4P-001 was able to inhibit SDF-1α-mediated calcium flux in these carboxy-terminated variants. .. These data further indicate that X4P-001 acts through interaction with the extracellular space of CXCR4. Furthermore, from the perspective of X4P-001 as a potential treatment option for WHIM syndrome, it is important that X4P-001 can inhibit multiple variants of CXCR4.

Furthermore, in the presence of an increasing amount of X4P-001, a dose / response comparison of SDF-1α in a calcium flux assay showed that X4P-001 was an allosteric inhibitor of CXCR4 [Mosi]. 2012]. Therefore, based on the inhibition mediated by non-competitive binding, the degree of inhibition depends only on the concentration of X4P-001 and not on the concentration of SDF-1α ligand.

In vivo Pharmacology The major in vivo pharmacological effect of X4P-001 is the recruitment of leukocytes (WBC) from the bone marrow. Three studies demonstrating WBC recruitment from the bone marrow of Beagle dogs and C3W / HeJ mice are summarized below.

Hematological effects in male Beagle dogs Three fasted male Beagle dogs have a volume of 1 mL / kg and dose levels of 5, 15 and 35 mg / kg (one per dose level). Dogs) received a single dose of X4P-001 in aqueous solution by oral gastrointestinal feeding. Blood samples (each approximately 3 mL), and by direct venipuncture from the jugular vein to give at multiple time points from each animal, using a Vacutainer (R) tubes containing _K 3 EDTA as anticoagulant Collected. Blood samples were obtained before and after dose 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 7, 12, and 24 hours. Blood samples were stored at ambient room temperature prior to automatic differential analysis.

Body weight was determined prior to dosing on the day of study administration. Animals were observed at least once daily and during blood sampling.

Hematological parameters included:
White blood cell count (WBC)
Leukocyte fraction (absolute and relative)
・ Neutrophils, lymphocytes, monocytes, eosinophils, basophils, large unstained cells (LUC)
・ Hematocrit (HCT)
・ Hemoglobin (HGB)
-Mean corpuscular hemoglobin (MCH)
Mean corpuscular hemoglobin concentration (MCHC)
Mean corpuscular volume (MCV)
・ Platelet count (PLT)
Red blood cell count (RBC)

Results The effect of X4P-001 on WBC and absolute neutrophil and lymphocyte counts is shown in FIG. The maximum increase in WBC occurred 4-12 hours after dose. Peak elevations ranged from 1.8-2.9 times baseline values at dose levels of 15 and 35 mg / kg, with somewhat lower (1.5-fold) increases observed at dose levels of 5 mg / kg. Was done. Limited by the small sample size, these results suggest that maximum increase can be achieved at higher dose levels. WBC, neutrophil, and lymphocyte counts remained elevated at dose levels of 15 and 35 mg / kg over 24 hours, with evidence of return to baseline. No other hematological effects were observed.

28-day oral (capsule) study in Beagle dogs with a 14-day recovery period 28-day GLP oral (capsule) toxicity in male and female Beagle dogs using X4P-001. Academic studies were conducted and X4P-001 was administered twice daily (at least at 7-hour intervals) for 28 days with oral capsules and hematological effects were observed. A subset of treated animals was evaluated after a 14-day recovery period. Table 3 presents the protocol design and Table 4 presents the evaluation schedule.

As shown in Table 5 below, an increase in absolute numbers for neutrophils, lymphocytes, and monocytes was observed at the end (day 28), which was larger and statistically significant in females. It was a tendency. These changes were considered consistent with the pharmacological effects of X4P-001. After a 14-day recovery period (evaluated only in the 100 mg / kg dose group), all hematological results returned to normal levels.

Hematological effects of mouse X4P-001 Further studies were conducted to determine whether X4P-001 recruits mouse precursors / stem cells. All experiments were performed on C3W / HeJ mice. X4P-001 and AMD3100 / Prelixahol were administered by single subcutaneous injection at the doses described below. The mobilization capacity of X4P-001 was assessed by the number of granulocyte macrophages (CFU-GM), erythrocytes (BFU-E) and pluripotent (CFU-GEMM) progenitor cells per mL of blood. To form colonies in vitro by combining lU / mL rhu EPO, 50 ng / mL rhu SLF, 5% vol / vol pokeweed mitogen mouse splenic cell conditioned medium (PWMSCM), and 0.1 mM hemin. Stimulated the progenitor cells. Plates were scored 7 days after incubation in a humidified chamber with _{5% CO 2} (5% CO ₂ ) reduced at 37 ° C.

Results X4P-001 recruited progenitor cells in C3H / HeJ mice after a single subcutaneous injection. In the first experiment (data shown in Table 6), mice received a dose of 5 mg / kg and had progenitor cell counts in circulating blood at various time points (0.25, 0.5, 1, 2, 6 and). 24 hours). Peak recruitment of nucleated cells occurred approximately 1-2 hours after injection. The peak increases in CFU-GM, BFU-E and CFU-GEMM were 4.21 times (30 minutes) and 2.49 to 2.54 times (30 to 30), respectively, with respect to the control (injection of saline). 60 minutes), and 2.58 to 2.67 times (30 to 60 minutes).

An X4P-001 dose response was performed by measuring the number of circulating progenitor cells in the blood 1 hour after injection at various doses (1.5, 2.5, 5, 10 and 20 mg / kg). As shown in Table 7, there appears to be an upper limit on the number of progenitor cells that can be mobilized with X4P-001, exemplified by the fold increase of CFU-GM. The number of CFU-GM in the circulating blood increased dose-dependently with a peak multiple increase of 6.0-7.7 relative to a control of 5-20 mg / kg. Increases in peak multiples of 2.3 and 3.8 for BFU-E and CFU-GEMM were observed at 10 mg / kg, respectively. For X4P-001 at doses less than 5 mg / kg, multiple increases in BFU-E and CFU-GEMM numbers were not statistically significant.

A final experiment was performed to compare the progenitor cell recruitment capacity of X4P-001 and AMD3100 / Prelixaform. Both drugs were subcutaneously administered at a dose of 5 mg / kg, and the number of progenitor cells in the circulating blood was 0.25, 0.5, 1 and 2 hours after injection, compared to X4P-001 at 1 hour after injection. AMD3100 at one time point (peak of mobilization for AMD3100, no data shown) was measured. As shown in Table 8 compared to multiple increases in CFU-GM, BFU-E, and CFU-GEMM, AMD3100 yielded maximum increases of 9/11, 3.12, and 4.35, respectively, while X4P. The peak mobilizations at -001 were 3.56, 2.84 and 3.21 respectively.

Conclusions from in vivo studies Single oral doses of 5, 15, and 35 mg / kg X4P-001 in Beagle dogs resulted in increased levels of total circulating WBC, neutrophils, and lymphocytes. The increase consistently appeared at 4 hours and typically peaked at 12 hours, sometimes earlier. At 5 mg / kg, all three cell numbers increased to 1.47 times baseline. At 15 mg / kg, neutrophils increased up to 1.8-fold, lymphocytes increased up to 2.9-fold, and at 35 mg / kg, neutrophils increased up to 2.7-fold and lymphocytes increased up to 1.9-fold.

In a multi-dose toxicity study in dogs, the hematological effects after 28 days were qualitatively and quantitatively consistent with the findings in a single-dose study in Beagle dogs.

In C3H / HeJ mice, X4P-001 increased the number of circulating progenitor cells in a dose-dependent manner up to subcutaneous injection at doses of 5-10 mg / kg.

(Example 2: Clinical: Patient to be treated)
Patients who may be treated by the present invention include patients who have been diagnosed with WHIMS or MKX, and patients who show characteristic mutations in the CXCR4 gene thereof. Other patients who may benefit from the present invention may include individuals showing the following screening criteria:

Neutropenia (ANC ≤400 or ≤600 / μL) and / or Lymphocytopenia (ALC≤650 or ≤1000 / μL) -The latter is not characteristic of other chronic neutropenia.

Neutropenia and chronic warts,

Bone marrow cell retention of bone marrow puncture fluid,

Patients who meet the above criteria are genetically screened for MKX. Patients with characteristic mutations in CXCR4 are most likely to benefit from treatment according to the invention.

Therefore, the effect of X4P-001 is expected to be highest in patients with myelogenous cell retention associated with CXCR4 mutations. In addition, patients who may benefit from the treatment according to the invention include individuals showing the following screening criteria:
1. 1. 2. Have a CXCR4 mutation that confirms a genotype consistent with WHIM syndrome. At least two independent blood samples collected over a period of up to 14 days with ANC ≤400 and ≤600 / μL, and ALC≤650 and / or ≤1000 / μL.
3. 3. Has one of the following findings:
Bone marrow puncture or biopsy showing myeloid cell retention-Peripheral WBC numbers showing <900 / μL absolute neutrophil count and / or <1,500 / μL absolute lymphocyte count (signs of acute infection) Or ≧ 2 independent samples if obtained asymptomatic and have not received G- or GM-CSF within the last 7 days).

Examples of candidate endpoints based on 6 months with treatment compared to the previous 6 months without treatment include:
・ 50% reduction in hospitalization ・ 50% reduction in infections requiring a systemic antibiotic course ・ 50% reduction in the area including warts on the skin ・ Persistent increase in circulating neutrophils (eg, evaluation) At least 85%, ANC> 600 / μL, ANC> 800 / μL, ANC> 1000 / μL, or ANC> 1,200 / μL)
Persistent increase in circulating lymphocytes (eg, ALC> 1000 cells / μL, ALC> 1,200 cells / μL, or ALC> 1,500 cells / μL in at least 85% of the assessment).
-Achieve that level for a protective antibody in response to at least two previously administered approved vaccines without achieving a predetermined level.
・ 50% reduction in the number of days absent from work or school due to infection ・ Sustained increase in circulating neutrophils.

Not all endpoints apply to all patients, and similarly, not all patients with WHIM show the same clinical manifestation. However, all patients present at least one clinical metric and one laboratory metric.

Patients are preferably started with oral treatment with X4P-001 25 mg once daily, 25 mg twice daily, or 50 mg once daily. Dose reduction in toxic events (may be by increasing the interval; eg, every other day or twice a week), or dose increase in events of inappropriate response (eg, once daily) Preparations are made for> 50 mg, or higher daily doses, eg 100 mg / day or 150 mg / day).

An exemplary initial dosage is X4P-001 25 mg capsules given orally in the morning in a fasted state with no food or beverage (excluding water) that lasts up to 2 hours after the dose and after midnight. In a twice-daily dosing regimen, capsules are preferably given orally at 12-hour intervals.

(Example 3: Clinical treatment regimen)
Dosing regimen for patients with WHIM syndrome X4P-001 is orally administered at a prescribed dose of 25 mg or 50 mg daily. Patients are instructed on both the dosing schedule and food or beverage requirements close to the time of dosing.

Dosing schedule. The first daily dose is taken in the morning. For twice daily dosing, the dose should be taken at 12 hour intervals. Dosing should be the same time ± 2 hours each day.

Food restrictions. Absorption is affected by food and the patient is instructed to:

About the morning dose:

・ No food or beverage (excluding water) from midnight to dosing

・ No food or drink (excluding water) for 2 hours after dosing.

Dosing of X4P-001 may be adjusted by the physician as appropriate. The dose of X4P-001 may be reduced at the discretion of the physician. If a patient receiving X4P-001 experiences a Grade> 2 adverse event, the dose of X4P-001 may be reduced at the discretion of the physician. If the patient successfully completes the first 2-4 weeks of treatment, i.e., does not experience any adverse events beyond grade 2, the daily dose of X4P-001 is increased in line with the physician's discretion. You may.

Alternative medication regimen for patients with WHIM syndrome Initial absolute neutrophil count (ANC) (neutropenia) (ANC <400 / μL or <600 / μL) and / or absolute lymphocyte count (ALC) in patients ) (Lymphocytopenia) (ALC <650 / μL or <1000 / μL) is measured. [Note-The latter is not characteristic of other chronic neutropenia]. If the patient exhibits less than 400 / μL or less than 600 / μL ANC and / or the ALC remains less than 650 / μL or 1000 / μL, treatment with X4P-001 is initiated. Patients begin treatment with X4P-001 25 mg once daily, orally, 25 mg twice daily, orally, or 50 mg once daily orally. .. Dose reduction (eg, every other day or twice a week, which may be by increasing the interval) or discontinuation of administration in toxic events, or dose increase (eg, in events of inappropriate response) Preparations are made to> 50 mg daily, or higher daily doses).

ANC and ALC are monitored monthly, preferably biweekly. If ANC> 400 / μL or> 600 / μL and / or ALC> 650 / μL or> 1000 / μL are achieved, the patient will continue with the original daily dosing regimen. If ANC remains less than 400 / μL or 600 / μL and / or ALC remains less than 650 / μL or 1000 / μL and the patient does not show any severe adverse effects. The patient's dose will be increased by 25 mg or 50 mg daily [or 25 mg twice daily, orally, at 12-hour intervals].

At an increased dose of 50 mg / μL per day, patients will continue to be monitored monthly or preferably biweekly. If ANC ≧ 400 / μL or ≧ 600 / μL, ALC ≧ 650 / μL or ≧ 1000 / μL (without severe adverse effects) is achieved, the patient continues with an increased dosing regimen. It will be. ANC remains less than 400 / μL or 600 / μL and / or ALC remains less than 650 / μL or 1000 / μL (patients show no severe adverse effects) If so, the patient's dose will be further increased by an additional 25 mg or 50 mg per day.

The above procedure to increase the daily dosing regimen allows patients to perform ANC ≧ 400 / μL or ≧ 600 / μL and / or ALC ≧ 650 / μL or ≧ 1000 (without severe adverse effects). It may be repeated until an individual / μL is achieved or until the patient is treated with the maximum tolerated daily dose.

Alternatively, ANC and ALC are analyzed as sub-curve areas (AUC) for pre-specified clinically meaningful thresholds of 400 / μL or 600 / μL and 650 / μL or 1000 / μL, respectively. .. The 24-hour AUC is calculated using the trapezoidal method, where the area above the threshold is positive and the area below the threshold is negative. _{150 mg in patients with AUC ANC} <2000 cells / hour / μL or AUC _ALC <5000 cells / hour / μL on a monthly or biweekly assessment
Increase the daily dose of X4P-001 by 25 mg or 50 mg increments up to the maximum dose of QD. Since ANC and ALC in WHIM patients are significantly affected by acute infection, AUC monitoring may be performed alone or with antibiotics, G-CSF or IVIG treatment until such patients remain afebrile for at least 2 weeks. Should be delayed or discontinued in patients with acute infections.

At any time, if a patient experiences adverse effects, preparations are made for dose reduction (ie, lowering the dosage and / or increasing the interval between drug doses) or discontinuing administration. In addition, the treating physician will use expert judgment and discretion in determining the starting dose, and the best method of titrating the appropriate dose of X4P-001 for any individual patient. May be.

An exemplary composition of X4P-001 25 mg capsules that may be used is shown in Table 9 below.

(Example 4: Evaluation of treatment effect)
Analyze circulating leukocyte whole blood samples for:

Differential counting of CBC and absolute lymphocytes by standard laboratory methods, including WBC numbers, including absolute numbers of lymphocytes, neutrophils, and CD34 + cells. Number and proportion of patients achieving ANC> 1,500 / μL, ALC> 900 / μL. Absolute increase in blood neutrophil count from pretreatment baseline for each subject, including the maximum observed at post-dose time and the maximum observed before dose in a stable drug administration regimen. These results are compared with data from healthy adults treated with X4P-001.

Peripheral blood monocytic cell (PBMC) subpopulations by flow cytometry are shown in Table 10 below.

Immunoglobulin and Specific Antibodies Serum samples are analyzed for levels of specific antibodies selected against total IgG, IgG subclasses, IgA, and IgM, as well as conventional vaccine antigens (Table 11).

Investigate the following parameters:
-Increased IgG, IgA, and IgM levels

For patients with a sub-protective titer of an antibody specific for an approved microbial vaccine, clinicians and patients will decide on vaccination and analyze the development of protective titers after vaccination. be able to.

Bone marrow aspiration fluid Bone marrow aspiration fluid is obtained from patients who consent to screening after 4 and 20 weeks of treatment. The puncture fluid is examined by a blinded hematopathologist and graded for cell solidity and myelogenous cell retention. If sufficient material is available, analyze the sample for markers of neutrophil apoptosis and lymphocyte subpopulation.

Investigate the following parameters:
・ Decrease in cell excess ・ Decrease in apoptotic WBC fraction

Clinical evaluation warts. Warts are monitored by photographs and / or records of lesion location, number, and size.

infection. Measure body temperature twice daily, develop fever, encourage a doctor's visit, request antibiotics, or investigate signs or symptoms of infection with hospitalization and compare with the year before treatment.

Pharmacokinetic Assessment If desired, a pharmacokinetic assessment of blood samples may be performed on plasma levels of X4P-001. Collect blood samples on schedule. Samples are analyzed for X4P-001 concentration using reverse phase high performance liquid chromatography (RP-HPLC) with MS / MS detection. The validation range of this biological analysis method is 30 to 3,000 ng / mL in plasma.

Pharmacokinetics (PK) and Pharmacodynamics (PD). To assess the pharmacokinetic properties of treatment with X4P-001, the level of X4P-001, PK samples are obtained for all patients in Part A as follows:
Day 1: 30, 60, 90 minutes before and after dose (± 10%, respectively) and 2, 3, 4 hours (± 15 minutes, respectively)
5th week visit: 30, 60, 90 minutes before and after dose (± 10%, respectively) and 2, 3, 4, 8 hours (± 15 minutes, respectively)
9th and 13th week visits: before dose

The visit is planned early that day and the patient is instructed to fast and arrive at the clinic without taking the morning dose of X4P-001.

PK is analyzed by patient and dosing regimen over the previous week using descriptive statistics for AUC, Cmax, and Cmin.

Additional sampling days may be added if the results suggest that either (a) progression of accumulation beyond week 5 or (b) specific PK parameters are associated with adverse effects.

PD samples will be collected at the 1st and 5th week visits at the same time as the PK samples (see above) schedule for:
• Total leukocyte (WBC) count • Circulating CD34 + positive cell count • Assessment may include samples analyzed by flow cytometry for the PBMC subpopulation.

If sample yield allows, an immunomodulatory subset of additional studies may be analyzed (see Table 11).

Of course, the treating physician will use any evaluation parameters (eg, desired levels of ANC and ALC) in determining the professional judgment and discretion, as well as any established standard treatment, treatment regimen for any individual patient. You may apply whether it should be used.

Claims (1)

The invention described in the specification.

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